EP0835140A2 - Polyaminosäuren-metallkomplexe und ihre anwendung in diagnostischer bilderzeugung - Google Patents

Polyaminosäuren-metallkomplexe und ihre anwendung in diagnostischer bilderzeugung

Info

Publication number
EP0835140A2
EP0835140A2 EP96924020A EP96924020A EP0835140A2 EP 0835140 A2 EP0835140 A2 EP 0835140A2 EP 96924020 A EP96924020 A EP 96924020A EP 96924020 A EP96924020 A EP 96924020A EP 0835140 A2 EP0835140 A2 EP 0835140A2
Authority
EP
European Patent Office
Prior art keywords
formula
solution
complex according
choh
aqueous
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP96924020A
Other languages
English (en)
French (fr)
Other versions
EP0835140B1 (de
Inventor
Dominique Meyer
Olivier Rousseaux
Michel Schaefer
Christian Simonot
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guerbet SA
Original Assignee
Guerbet SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guerbet SA filed Critical Guerbet SA
Publication of EP0835140A2 publication Critical patent/EP0835140A2/de
Application granted granted Critical
Publication of EP0835140B1 publication Critical patent/EP0835140B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0442—Polymeric X-ray contrast-enhancing agent comprising a halogenated group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
    • A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings

Definitions

  • the present invention relates to metal complexes of polyamino acids, their preparation process and their use in diagnostic imaging.
  • These compounds are branched derivatives of gadoteric acid, sold in the form of meglumine salt under the brand Dotarem® as a contrast agent for magnetic resonance imaging.
  • the meglumine gadoterate is a stable complex whose spin-network relaxivity at 37 " C and 20 MHz is approximately 3.5 mM " V, of the same order of magnitude as that of other contrast agents on the market.
  • the gadolinium complexes according to the invention have relaxivities R, greater than 20 rnM ' V 1 ; this allows the subject to be administered, in order to obtain the same signal intensity, a diagnostic composition whose molar concentration of complexed Gd 3+ , and therefore of compound according to the invention, is 6 times and even 10 times lower than the concentrations currently used in the clinic.
  • these complexes have bromine or iodine atoms and are opaque to X-rays and they are sufficiently soluble, in particular by the presence of hydrophilic groups around the aromatic nuclei, to be used in radiology conventional or in dichromography.
  • the compounds of the invention have the formula
  • R represents a group
  • R is H, (C ⁇ C ⁇ alkyl or (C 2 -C 8 ) mono- or polyhydroxyalkyl and
  • R 2 is (C 2 -C 8 ) mono- or polyhydroxyalkyl, or else
  • R is H and R 2 is a group
  • R ' ⁇ and R' 2 independently taking any of the meanings given for R, and R 2 , excluding A, it being understood that -CO-NR-R., Or - CO-NR ' T R' J have at least 2 hydroxyl groups, and M represents H or an organic or inorganic cation.
  • M represents H or an organic or inorganic cation.
  • the alkyl groups can be linear or branched.
  • the compounds of formula I can be prepared by the action of the amine of formula II
  • A can be obtained by reaction of HNR-R-. with the diacid dichloride of formula IV:
  • the amines of formula II for which R 2 represents A and R represents H are simply obtained by reacting an amine of formula H 2 NA with the diacid dichloride of formula IV previously N-protected. It will be noted that the amine H 2 NA, which corresponds to an amine of formula II in which R 2 is distinct from A, can be prepared according to the method proposed above.
  • contrast agent compositions for magnetic resonance imaging which contain a compound of formula I in a pharmaceutically acceptable vehicle.
  • Their pharmaceutical form will be adapted to the route of administration.
  • compositions of contrast agents will be aqueous solutions of physiologically acceptable salts of the complex of formula I.
  • the compositions of the invention may also contain stabilizers, various additives intended to make the solution isotonic or make it possible to fix its pH, as well as any other type of additive commonly used in the art.
  • the concentration of the composition will be adapted to the route and the area of administration; it will generally be between 0.01 M and 0.5 M and preferably between 0.05 M and 0.1 M.
  • the unit dose will obviously depend on the structure of the complex and the nature of the examination; in general, 0.005 mmol / kg to 0.1 mmol / kg will be administered.
  • the methanol is removed under reduced pressure and the aqueous phase extracted with methylene chloride, before introducing therein about 800 ml of cationic ion exchange resin Amberlite®, marketed by Rohm and Haas, under the designation IRC 50 (weak acid ).
  • the resin is separated and introduced into a column; the sought product is isolated by elution using 4 I of an aqueous 3N acetic acid solution and then 4 I of 6N solution.
  • 29.4 g of the octaacid previously obtained are suspended in 530 ml of water, with 15.8 g of GdCI 3 , 6 H 2 O; with stirring, an aqueous 1N NaOH solution is introduced slowly until the pH of the medium is stabilized at 6.5.
  • the medium is then filtered through a Millipore® filter with a 0.45 ⁇ m mesh and the filtrate concentrated to dryness. After drying 49.3 g of the sodium salt of the gadolinium complex of formula III is obtained, in the form of a beige solid containing the NaCl formed during the complexation.
  • This product can be purified by precipitation in aqueous ethanol and treatment, to remove an excess of uncomplexed Gd 3+ , with a chelating resin such as that sold by Biorad Laborato ⁇ ries under the brand CHELEX.
  • Relaxivity R, (37 ° C; 20 MHz) 5.9 mM ' V;
  • a solution, in 1000 ml of dimethylacetamide, of 104 g of the above acid dichloride, 208 g of disorbitylamine and 50 ml of triethylamine is kept at 80 ° C. for 5 hours.
  • the precipitate formed is separated and the solvent is removed by distillation under reduced pressure; the residue is dissolved in water at pH 3 and brought into contact with 750 ml of resin cationic ion exchange Amberlite® sold by Rohm and Haas under the name IRN 77 (strong acid).
  • the resin is separated and 17 ml of hydrazine hydrate are introduced into the aqueous solution (700 ml) of the purified diamide.
  • the medium is acidified at room temperature by the addition of 26 ml of a 10N aqueous hydrochloric acid solution.
  • the precipitate formed is isolated and the solution is passed through a column of 500 ml of a weak ion exchange resin (Amberlite® IRA 67) then 80 ml of a weak cationic resin (Amberlite® IRC 50); the solution obtained is treated with 4 I of strong acid Amberlite® resin, on which the final product is fixed; it is eluted with an aqueous NH 4 OH solution.
  • Amine II is obtained with 70% yield in the form of a beige solid.
  • the starting 5-amino-2,4,6-tribromoisophthalic acid is prepared with 85% yield per action of 100 ml of bromine on a solution in 1300 ml of water and 380 ml of concentrated hydrochloric acid, of 87 g 5-aminoisophthalic acid.
  • the corresponding acid dichloride is prepared conventionally by the action of SOCI 2 on the corresponding diacid with 88% yield.
  • aqueous solution which contains the expected phthalimide (80% of theory), is treated as in the previous preparation by hydrazine hydrate to give the expected amine II with a yield of 85%.
  • a solution of 37.5 g of the compound previously isolated in 130 ml of water and 2 ml of aqueous 35% hydrazine solution is kept at 80 ° C. for 5 hours. After cooling, the medium is brought to pH 1 by addition of 10N aqueous HCl and then chromatography successively on 100 ml of cationic (IRN77) and anionic (IRA67) Amberlite® resins and on 500 ml of a polystyrenic acid resin, cation exchange type IMAC HP222 marketed by Rohm and Haas, from which the sought product is eluted by a aqueous NH 4 OH solution 3M and then isolated by precipitation in ethanol after concentration.
  • IRN77 cationic
  • IRA67 anionic
  • 75 g of the product previously obtained are introduced at 80 ° C. into 50 ml of water containing 1.43 ml of 35% aqueous hydrazine solution and the mixture is maintained at this temperature for 5 hours before being brought to pH. 1 by addition of 10N aqueous HCl.
  • the precipitate is separated and the aqueous phase is chromatographed on 100 ml of cationic resin H + Amberlite® IRC50 then on 200 ml of anionic resin OH " Amberlite® IRA67.
  • reaction medium to which 50 ml of water has been added is subjected to ultrafiltration with a mini-cassette cassette of the nova type sold by the company Filtron (U.S.A.) comprising a polyethersulfone membrane of 5 KDa cut-off threshold.
  • Filtron U.S.A.
  • the reaction can also be carried out at around 40 ° C., optionally in the presence of a catalytic amount of sodium salt of (N-hydroxysuccinimidyl) -3-sulfonic acid.
  • the product can be purified by precipitation in isopropanol.
  • the solution is ultrafiltered as previously on a membrane of 1 kdalton cut-off threshold. After evaporation of the water, 15 g of the sought product are obtained in the form of a white powder.
  • HPLC operating conditions of Example 2. Retention time: 3 minutes.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Radiology & Medical Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Polyamides (AREA)
EP96924020A 1995-06-29 1996-06-25 Polyaminosäuren-metallkomplexe und ihre anwendung in diagnostischer bilderzeugung Expired - Lifetime EP0835140B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9507860A FR2736051B3 (fr) 1995-06-29 1995-06-29 Complexes metalliques de polyaminoacides, leur procede de preparation et leur utilisation en imagerie diagnostique
FR9507860 1995-06-29
PCT/FR1996/000992 WO1997001359A2 (fr) 1995-06-29 1996-06-25 Complexes metalliques de polyaminooxydes et leur utilisation en imagerie diagnostique

Publications (2)

Publication Number Publication Date
EP0835140A2 true EP0835140A2 (de) 1998-04-15
EP0835140B1 EP0835140B1 (de) 2001-10-31

Family

ID=9480531

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96924020A Expired - Lifetime EP0835140B1 (de) 1995-06-29 1996-06-25 Polyaminosäuren-metallkomplexe und ihre anwendung in diagnostischer bilderzeugung

Country Status (21)

Country Link
US (1) US5886158A (de)
EP (1) EP0835140B1 (de)
JP (1) JPH11508550A (de)
KR (1) KR19990028556A (de)
CN (1) CN1074934C (de)
AT (1) ATE207762T1 (de)
AU (1) AU708180B2 (de)
BR (1) BR9609519A (de)
CA (1) CA2222697A1 (de)
CZ (1) CZ414197A3 (de)
DE (1) DE69616548T2 (de)
EA (1) EA000378B1 (de)
FR (1) FR2736051B3 (de)
HU (1) HUP9900449A3 (de)
IL (1) IL122621A0 (de)
NO (1) NO976098L (de)
NZ (1) NZ312720A (de)
PL (1) PL325531A1 (de)
SK (1) SK282197B6 (de)
TR (1) TR199701716T1 (de)
WO (1) WO1997001359A2 (de)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2772025B1 (fr) * 1997-12-10 2000-03-03 Guerbet Sa Chelates metalliques de macrocycles polyaminocarboxyliques et leur application a l'imagerie par resonance magnetique
IT1297035B1 (it) 1997-12-30 1999-08-03 Bracco Spa Derivati dell'acido 1,4,7,10-tetraazaciclododecan-1,4-diacetico
FR2793795B1 (fr) * 1999-05-21 2001-08-03 Guerbet Sa Isomeres de tetramides du complexe de gadolinium de l'acide (1,4,7,10-tetrazacyclododecane)1,4,7,10-tetra(2-glutarique) leur procede de preparation et leur application en imagerie medicale
FR2794744B1 (fr) * 1999-06-09 2001-09-21 Guerbet Sa Complexes metalliques de polyaminoacides bicycliques, leur procede de preparation et leur application en imagerie medicale
KR100309386B1 (ko) * 1999-08-04 2001-09-26 이계안 파트타임 4륜구동차량의 자동절환식 차동장치
FR2836916B1 (fr) * 2002-03-05 2004-06-11 Guerbet Sa Oligomeres de chelates de gadolinium, leur application comme produits de contraste en imagerie par resonance magnetique et leurs intermediaires de synthese
DE10307759B3 (de) * 2003-02-19 2004-11-18 Schering Ag Trimere makrocyclisch substituierte Benzolderivate, deren Herstellung und Verwendung als Kontrastmittel sowie diese enthaltende pharmazeutische Mittel
FR2856689A1 (fr) * 2003-06-25 2004-12-31 Guerbet Sa Composes specifiques a forte relaxivite
US20060275217A1 (en) * 2005-05-06 2006-12-07 Caravan Peter D Chemical exchange saturation transfer contrast agents
KR101193686B1 (ko) * 2005-08-29 2012-10-22 니혼앗짜쿠단시세이소 가부시키가이샤 전기 커넥터 및 액정 표시 장치
DE102007058220A1 (de) 2007-12-03 2009-06-04 Bayer Schering Pharma Aktiengesellschaft Dimere macrocyclisch substituierte Benzolderivate
US20090208421A1 (en) * 2008-02-19 2009-08-20 Dominique Meyer Process for preparing a pharmaceutical formulation of contrast agents
MX2014001623A (es) 2011-08-10 2015-03-09 Digna Biotech Sl Uso de la cardiotofina-1 para el tratamiento de enfermedades renales.
WO2017165841A1 (en) 2016-03-25 2017-09-28 Nanoprobes, Inc. Iodine-based particles

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8916782D0 (en) * 1989-07-21 1989-09-06 Nycomed As Compositions
US5116599A (en) * 1989-07-31 1992-05-26 Johns Hopkins Univ. Perfluoro-t-butyl-containing compounds for use in fluorine-19 nmr and/or mri
US5324503A (en) * 1992-02-06 1994-06-28 Mallinckrodt Medical, Inc. Iodo-phenylated chelates for x-ray contrast
WO1994027644A1 (en) * 1993-06-02 1994-12-08 Bracco S.P.A. Iodinated paramagnetic chelates, and their use as contrast agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9701359A2 *

Also Published As

Publication number Publication date
NZ312720A (en) 1999-04-29
EP0835140B1 (de) 2001-10-31
AU708180B2 (en) 1999-07-29
CN1074934C (zh) 2001-11-21
FR2736051B3 (fr) 1997-09-26
JPH11508550A (ja) 1999-07-27
DE69616548D1 (de) 2001-12-06
US5886158A (en) 1999-03-23
PL325531A1 (en) 1998-08-03
ATE207762T1 (de) 2001-11-15
WO1997001359A2 (fr) 1997-01-16
HUP9900449A2 (hu) 1999-06-28
TR199701716T1 (xx) 1998-04-21
EA199800101A1 (ru) 1998-08-27
WO1997001359A3 (fr) 1997-05-22
BR9609519A (pt) 1999-02-23
CA2222697A1 (fr) 1997-01-16
CN1189778A (zh) 1998-08-05
HUP9900449A3 (en) 2001-05-28
NO976098L (no) 1998-02-27
FR2736051A1 (fr) 1997-01-03
SK173797A3 (en) 1998-06-03
MX9710380A (es) 1998-07-31
DE69616548T2 (de) 2002-07-18
IL122621A0 (en) 1998-08-16
CZ414197A3 (cs) 1998-03-18
NO976098D0 (no) 1997-12-29
EA000378B1 (ru) 1999-06-24
KR19990028556A (ko) 1999-04-15
AU6461696A (en) 1997-01-30
SK282197B6 (sk) 2001-12-03

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